Tau proteins normally stabilize microtubules in neuronal processes in the brain. During the course of Alzheimer's disease and certain other neurodegenerative diseases, these proteins dissociate from the microtubule and begin to aggregate within cell bodies of neurons and glial cells in specific disease-related regions of the brain. This process is accompanied by an inflammatory response, one result of which is the nitration and oxidative crosslinking of certain proteins. We have discovered that tau gets nitrated predominantly at specific tyrosine residues in AD and related frontotemporal dementias;moreover, tau also can be crosslinked by dityrosine bonds. We propose to use biochemical modeling studies to determine the role of nitration in tau filament formation and to produce antibodies that only recognize specific nitrated residues and dityrosine crosslinked areas on tau for use in following this process in the brains of patients that died with AD or another tauopathy. Specifically, we will: 1. Study the affect of nitration on the assembly of each of the tau isoforms;2. Study the inhibition of assembly of normal tau by tau nitrated at specific sites;3. Use immunohistochemistry and laser scanning confocal microscopy with our specific antibodies to different nitrated sites on tau to assess the timing and role of nitrative events during the course of AD and other tauopathies. We will also produce monoclonal antibodies to additional nitrated sites on tau and assess them in diseased brains as well;and, 4. Manufacture monoclonal antibodies to dityrosine cross-linked tau in order to determine when this event occurs during the course of AD and other tauopathies. We hypothesize that site-specific tau nitration and dityrosine cross-linking events represent key elements in the formation and stabilization of the fibrillar pathologies in AD and other tauopathies. Successful completion of these studies will contribute greatly to our understanding of the role of inflammation in AD and other tauopathies. PUBLIC HEALTH RELEVANCE: In maladies such as Alzheimer's disease and related dementias, proteins known as tau aggregate within the cell bodies of neurons and certain glial cells. This aggregation is accompanied by an inflammatory process that causes these proteins to be altered on amino acids called tyrosines. We propose to determine the function of these alterations in disease and to determine when and where they occur.